{
  "abstract": "Mechanisms linking CD33 variants to Alzheimer Disease (AD) are poorly defined. Here, we combine structural, cellular, and genetic analyses to delineate how the CD33 M splice isoform, upregulated in carriers of CD33 risk alleles, modulates microglial function. We show that CD33 M ectodomain dimerizes, enabling binding of large multi-sialylated molecules. We demonstrate that another AD risk protein - clusterin (CLU) ± Aβ oligomers (but not ApoE) binds with nanomolar avidity to CD33 M , but not CD33 m . We show that in human monocytes CD33 M :CLU binding induces CD33 M ITIM phosphorylation, recruits SHP-1, suppresses Aβ phagocytosis, and impairs clearance of amyloid plaques. We identify a soluble CD33 M ectodomain fragment (sCD33 M ) - absent from CD33 m -expressing cells - which could contribute to the role of CD33 M in AD. Genetic analyses confirm that CD33:CLU interaction modulates amyloid burden, cognition, and disease risk. These findings define a mechanistic CLU:Aβ:CD33 M axis, highlighting CD33 M dimerization and ligand-binding sites as potential therapeutic targets.",
  "abstract_shown": true,
  "affiliations": [
    "Cambridge Institute for Medical Research, Cambridge, UK",
    "Cambridge Institute for Medical Research, Welcome Trust/MRC Building, Cambridge Biomedical Campus, Hills Road, Cambridge, CB2 0XY, United Kingdom",
    "Department of Medical Biophysics, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada",
    "Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada",
    "Princess Margaret Cancer Centre, University Health Network, Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada",
    "Department of Medicine (Division of Neurology), University Health Network, Toronto, ON, Canada",
    "Department of Medicine (Neurology), Tanz Centre for Research in Neurodegenerative Diseases, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada",
    "Department of Medicine (Division of Neurology) and University Health Network, Toronto, ON, Canada",
    "Tanz Centre for Research in Neurodegenerative Diseases, Departments of Medicine (Neurology) and Medical Biophysics, University of Toronto",
    "Department of Psychiatry and Molecular Pharmacology and Therapeutics, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA",
    "Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, NY, USA",
    "Department of Psychiatry and Department of Molecular Pharmacology and Therapeutics, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA",
    "Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, NY 10032, USA",
    "Carol and Gene Ludwig Center for Research on Neurodegeneration, Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Department of Neurology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA",
    "Carol and Gene Ludwig Center for Research on Neurodegeneration, Taub Institute for Research on Alzheimer's Disease and the Aging Brain, The Gertrude H. Sergievsky Center, Departments of Neurology Columbia University Medical Center, 630 West 168th Street, New York, NY 10032, USA",
    "Division of Translational Neurobiology, Departments of Neurology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA",
    "Division of Translational Neurobiology, Departments of Neurology Columbia University Medical Center, 30 West 18th Street, New York, NY 10032, USA",
    "Center for Translational and Computational Neuroimmunology, Departments of Neurology Columbia University Medical Center, New York, NY, USA",
    "Center for Translational and Computational Neuroimmunology, Departments of Neurology Columbia University Medical Center, 630 West 168th Street, New York, NY 10032, USA",
    "Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA",
    "Sanford Burnham Prebys Medical Discovery Institute, 10901 N. Torrey Pines Road, La Jolla, CA 92037",
    "Department of Neurobiology, George S. Wise Faculty of Life Sciences, School of Neurobiology, Biochemistry and Biophysics, Tel Aviv University, Tel Aviv, Israel",
    "Department of Neurobiology, George S. Wise Faculty of Life Sciences, School of Neurobiology, Biochemistry and Biophysics, Tel Aviv University, Tel Aviv 678, Israel",
    "Department of Pediatric Oncology, Dana Farber Cancer Institute, and Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA, USA",
    "Department of Pediatric Oncology, Dana Farber Cancer Institute, and Division of Hematology/Oncology, Boston Children's Hospital, 300 Longwood Avenue Boston, MA 02115, USA",
    "MRC Laboratory of Molecular Biology, Cambridge, UK",
    "MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Francis Crick Ave, Cambridge CB2 OQH, United Kingdom",
    "Department of Molecular Genetics, Center for Translational Neurodegeneration Research9, University of Texas Southwestern, Dallas, TX, USA",
    "Department of Neuroscience, Neurology and Neurotherapeutics, University of Texas Southwestern, Dallas, TX, USA",
    "Departments of Neuroscience, Neurology and Neurotherapeutics, University of Texas Southwestern, Dallas, TX 75390",
    "School of Science, Faculty of Science, Medicine & Health, Molecular Horizons Research Institute, University of Wollongong, Wollongong, NSW, Australia",
    "School of Science, Faculty of Science, Medicine & Health, Molecular Horizons Research Institute, University of Wollongong, Northfields Avenue, Wollongong. NSW. 2522. AUSTRALIA",
    "Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA",
    "Department of Cell and Developmental Biology, Faculty of Medicine, and Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel",
    "Department of Cell and Developmental Biology, Faculty of Medicine, and Sagol School of Neuroscience, Tel Aviv University, Tel Aviv 69978, Israel",
    "Department of Psychiatry and Molecular Pharmacology and Therapeutics, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA. Wesley.Asher@nyspi.columbia.edu",
    "Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, NY, USA. Wesley.Asher@nyspi.columbia.edu",
    "Carol and Gene Ludwig Center for Research on Neurodegeneration, Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Department of Neurology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA. emb2280@cumc.columbia.edu",
    "Division of Translational Neurobiology, Departments of Neurology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA. emb2280@cumc.columbia.edu",
    "Cambridge Institute for Medical Research, Cambridge, UK. phs22@cam.ac.uk"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 50,
  "authors": [
    {
      "affs": [
        0,
        1
      ],
      "name": "Roger B. Dodd",
      "orcid": "0000-0003-4268-1863"
    },
    {
      "affs": [
        2,
        3,
        4
      ],
      "name": "Masahiro Enomoto",
      "orcid": "0000-0002-9411-2999"
    },
    {
      "affs": [
        5,
        6,
        7,
        8
      ],
      "name": "Ye Zhou",
      "orcid": "0000-0003-3861-3120"
    },
    {
      "affs": [
        5,
        6,
        7,
        8
      ],
      "name": "Kanayo Satoh",
      "orcid": "0000-0001-9684-239X"
    },
    {
      "affs": [
        5,
        6,
        7,
        8
      ],
      "name": "Yalun Zhang",
      "orcid": "0000-0002-4078-4087"
    },
    {
      "affs": [
        5,
        6,
        7,
        8
      ],
      "name": "Fusheng Chen",
      "orcid": "0000-0001-8525-4154"
    },
    {
      "affs": [
        5,
        6,
        7,
        8
      ],
      "name": "Beatrice Acheson"
    },
    {
      "affs": [
        5,
        6,
        7,
        8
      ],
      "name": "Deniz Ghaffari",
      "orcid": "0000-0001-5567-9581"
    },
    {
      "affs": [
        5,
        6,
        7,
        8
      ],
      "name": "Elizabeth Sayn-Wittgenstein",
      "orcid": "0009-0006-7497-3878"
    },
    {
      "affs": [
        9,
        10,
        11,
        12
      ],
      "name": "Jamie J. Manning",
      "orcid": "0000-0002-6945-2254"
    },
    {
      "affs": [
        9,
        10,
        11,
        12
      ],
      "name": "George V. Dukas",
      "orcid": "0009-0002-9738-9421"
    },
    {
      "affs": [
        13,
        14
      ],
      "name": "Ronak B. Patel",
      "orcid": "0000-0002-8871-6390"
    },
    {
      "affs": [
        13,
        14
      ],
      "name": "Alondra Schweizer Burguete",
      "orcid": "0000-0003-0324-3334"
    },
    {
      "affs": [
        13,
        14
      ],
      "name": "Mason J. Kralovec"
    },
    {
      "affs": [
        13,
        15,
        16
      ],
      "name": "Mamunur Rashid",
      "orcid": "0000-0001-6768-1814"
    },
    {
      "affs": [
        13,
        15,
        16
      ],
      "name": "Jennifer L. Hall",
      "orcid": "0000-0002-5103-5399"
    },
    {
      "affs": [
        13,
        15,
        16
      ],
      "name": "Kirstin A. Tamucci",
      "orcid": "0000-0002-7033-807X"
    },
    {
      "affs": [
        13,
        15,
        14
      ],
      "name": "Zena K. Chatila",
      "orcid": "0000-0002-4383-6305"
    },
    {
      "affs": [
        13,
        14
      ],
      "name": "Minghua Liu",
      "orcid": "0000-0001-6147-0565"
    },
    {
      "affs": [
        13,
        14
      ],
      "name": "Annie Lee",
      "orcid": "0000-0003-3726-6024"
    },
    {
      "affs": [
        13,
        14
      ],
      "name": "Badri Narayan Vardarajan",
      "orcid": "0000-0002-5560-4085"
    },
    {
      "affs": [
        17,
        18
      ],
      "name": "Mariko F. Taga",
      "orcid": "0000-0002-5791-2348"
    },
    {
      "affs": [
        19,
        20
      ],
      "name": "Sirkku Pollari",
      "orcid": "0000-0001-7066-7052"
    },
    {
      "affs": [
        21,
        22
      ],
      "name": "Alon Rabinovich"
    },
    {
      "affs": [
        23,
        24
      ],
      "name": "Cory D. Rillahan"
    },
    {
      "affs": [
        19,
        20
      ],
      "name": "Andrey A. Bobkov",
      "orcid": "0000-0002-9028-3635"
    },
    {
      "affs": [
        19,
        20
      ],
      "name": "Eduard A. Sergienko",
      "orcid": "0009-0003-2595-2227"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "William Meadows"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Seema Qamar",
      "orcid": "0000-0003-1189-206X"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Suzanne J. Randle",
      "orcid": "0009-0005-2133-9702"
    },
    {
      "affs": [
        25,
        26
      ],
      "name": "Christopher M. Johnson",
      "orcid": "0000-0002-1244-5926"
    },
    {
      "affs": [
        5,
        6,
        7,
        8
      ],
      "name": "Jean Sévalle"
    },
    {
      "affs": [
        5,
        6,
        7,
        8
      ],
      "name": "Jennifer K. Griffin",
      "orcid": "0000-0001-8390-7502"
    },
    {
      "affs": [
        5,
        6,
        7,
        8
      ],
      "name": "Christopher Böhm"
    },
    {
      "affs": [
        2,
        3,
        4
      ],
      "name": "Mitsuhiko Ikura",
      "orcid": "0000-0002-9524-1303"
    },
    {
      "affs": [
        27,
        28,
        29
      ],
      "name": "Xunde Xian",
      "orcid": "0000-0003-3059-1254"
    },
    {
      "affs": [
        27,
        28,
        29
      ],
      "name": "Joachim Herz",
      "orcid": "0000-0002-8506-3400"
    },
    {
      "affs": [
        30,
        31
      ],
      "name": "Megan A. Kelly",
      "orcid": "0000-0002-0877-126X"
    },
    {
      "affs": [
        30,
        31
      ],
      "name": "Jennifer West",
      "orcid": "0000-0001-8708-921X"
    },
    {
      "affs": [
        30,
        31
      ],
      "name": "Sandeep Satapathy",
      "orcid": "0000-0003-1479-1280"
    },
    {
      "affs": [
        30,
        31
      ],
      "name": "Mark R. Wilson",
      "orcid": "0000-0002-9551-7445"
    },
    {
      "affs": [
        9,
        10,
        11,
        12
      ],
      "name": "Jonathan A. Javitch",
      "orcid": "0000-0001-7395-2967"
    },
    {
      "affs": [
        2,
        6,
        7,
        8
      ],
      "name": "Paul Fraser",
      "orcid": "0000-0003-1227-4239"
    },
    {
      "affs": [
        32
      ],
      "name": "David A. Bennett",
      "orcid": "0000-0003-3689-554X"
    },
    {
      "affs": [
        17,
        18
      ],
      "name": "Philip L. De Jager",
      "orcid": "0000-0002-8057-2505"
    },
    {
      "affs": [
        33,
        34
      ],
      "name": "Zvi Fishelson",
      "orcid": "0000-0001-7097-6357"
    },
    {
      "affs": [
        33,
        21,
        34
      ],
      "name": "Dan Frenkel",
      "orcid": "0000-0002-7494-6857"
    },
    {
      "affs": [
        35,
        36,
        11,
        12
      ],
      "name": "Wesley B. Asher",
      "orcid": "0000-0001-7437-218X"
    },
    {
      "affs": [
        37,
        38,
        16
      ],
      "name": "Elizabeth M. Bradshaw",
      "orcid": "0000-0002-6766-4325"
    },
    {
      "affs": [
        39,
        1,
        14,
        7,
        8
      ],
      "name": "Peter St George‐Hyslop",
      "orcid": "0000-0003-0796-7209"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/6nczyry614cna.bib",
  "cited_by": 6,
  "doi": "10.1038/s41467-026-75140-3",
  "fulltext_url": null,
  "id": "6nczyry614cna",
  "issns": [
    "2041-1723"
  ],
  "landing_url": "https://doi.org/10.1038/s41467-026-75140-3",
  "language": "en",
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "journal",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "2804|Alzheimer's disease research and treatments"
    ]
  ],
  "openalex": "W4412800180",
  "pdf_url": "https://www.nature.com/articles/s41467-026-75140-3_reference.pdf",
  "pmcid": "PMC13507242",
  "pmid": "42469217",
  "published": "2026-07-17",
  "publisher": "Nature Portfolio",
  "ris": "https://research.draconitic.com/paper/6nczyry614cna.ris",
  "sources": [
    {
      "first_seen": "2026-11-13T13:21:09Z",
      "native_id": "W4412800180",
      "source": "openalex",
      "url": "https://doi.org/10.1038/s41467-026-75140-3"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "openalex:2804|Alzheimer's disease research and treatments",
      "subfield": "neuroscience"
    }
  ],
  "title": "CD33 and clusterin interact biophysically and genetically to modulate Alzheimer risk",
  "title_text": "CD33 and clusterin interact biophysically and genetically to modulate Alzheimer risk",
  "type": "peer-reviewed",
  "updated_at": "2026-11-13T13:21:09Z",
  "url": "https://research.draconitic.com/paper/6nczyry614cna",
  "venue": "Nature Communications",
  "versions": []
}